We have discovered that Esculentoside A (EsA) has potent anti-inflammatory effects including specific COX2 inhibition. Our preliminary studies and the associated patent apply to the use of EsA for the prevention of radiation-related inflammation (IR). We found that EsA was more effective than Celebrex at preventing and reducing acute radiation dermatitis and late soft tissue fibrosis, and EsA was as effective as dexamethasone at reducing radiation-induced brain edema. Side effects were similar or less than Celebrex(r). Studies in a standard model of inflammation are needed to establish the utility of EsA for autoimmune (e.g. rheumatoid arthritis) and other inflammatory disease (e.g. osteroarthritis). In our IR studies, the drug was administered i.p., and we need to confirm that EsA can be delivered effectively by other routes. Likewise, the therapeutic index must be determined. These basic requirements precede others required by the FDA before phase I and phase II testing can commence. We will focus on the following aims in Phase I: 1) test for beneficial anti-inflammatory effects of EsA in a standard arthritis model; 2) demonstrate that oral and other administrative routes have utility, and determine the optimal dose and ED50; and 3) measure the therapeutic window and side effect profile of EsA in mice. The study should broaden our knowledge of EsA and lay the foundation for development of this naturally existing anti-inflammatory agent. Relevance: While there is high demand for COX2 inhibitors, the recent observation that Vioxx(r) increases heart attacks and strokes has resulted in a great public health need for a new, less toxic and less expensive NSAID of the selective anti-COX2 class. Our preliminary studies indicate that EsA should not predispose patients to vascular events. While the leading COX2 inhibitor, Celebrex(r), has allergic cross-reactivity to sulfonamides, EsA should not.